Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)–induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4⁺ T cells in the peripheral blood, consistent with impaired CD4⁺ T cell responses to recall antigens in vitro. The proportion of effector memory CD8⁺ T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4⁺ T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.Kaposi sarcoma (KS) is an inflammatory neoplasm affecting cells of endothelial origin (Ganem, 2010) first described by Moritz Kaposi (Kaposi, 1872). The causal infectious agent of all known forms of KS is human herpes virus 8 (HHV-8), also known as KS-associated herpes virus (KSHV; Chang et al., 1994). More than 100 million people are infected with HHV-8, with a heterogeneous worldwide distribution (Plancoulaine et al., 2002). Infection with HHV-8 is asymptomatic in the vast majority of cases (Wang et al., 2001; Andreoni et al., 2002). Only a very small proportion of HHV-8–infected individuals develop KS in their lifetime (Davidovici et al., 2001). Acquired immunodeficiency is a strong KS-predisposing factor; HIV coinfection (epidemic KS) and transplantation-related immunosuppression (iatrogenic KS) increase the risk of KS by factors of at least 3,000 and 100, respectively (Jensen et al., 1999; Serraino et al., 2005; Shiels et al., 2011). Idiopathic cases of KS, striking otherwise healthy individuals with no overt immunological deficit, are mostly reported in the Mediterranean Basin (classic KS) and sub-Saharan Africa (endemic KS). Classic KS is typically an indolent disease of the skin occurring predominantly in the elderly (median age of onset: 65 yr; Iscovich et al., 2000). Classic KS is exceedingly rare in children, with fewer than 40 cases reported since 1960 (Dutz and Stout, 1960; Bisceglia et al., 1988; Akman et al., 1989; Zurrida et al., 1994; Landau et al., 2001; Ferrari et al., 2002; Hussein, 2008; Sahin et al., 2010; Salem et al., 2011; Cakir et al., 2013). The data available before the HIV epidemic suggest that endemic KS is usually more aggressive than the classic form, affecting a younger population (median age of onset: 40 yr), with frequent lymph node involvement (Boshoff and Weiss, 2001). Endemic KS in childhood was rare in Africa in the years before the HIV epidemic, although not as rare as the classic form (Taylor et al., 1972). The rarity of childhood KS contrasts with the relatively high seroprevalence of HHV-8 infection in children <15 yr of age in the Mediterranean region and in Sub-Saharan Africa (Mayama et al., 1998; Andreoni et al., 1999; Gessain et al., 1999). Furthermore, childhood KS, whether it is classic or endemic, runs a more aggressive and disseminated course in children than in adults (Dutz and Stout, 1960; Olweny et al., 1976). Thus, inherited or acquired host factors may underlie classic and endemic KS of childhood.Inherited immunodeficiencies have been described in two unrelated children with classic KS and other, concurrent, infectious phenotypes: autosomal recessive complete IFN-γ receptor-1 (IFN-γR1) deficiency in a Turkish child with KS and mycobacterial disease (Camcioglu et al., 2004) and X-linked recessive Wiskott–Aldrich syndrome (WAS) in a Tunisian child with KS and EBV lymphoma (Picard et al., 2006). The observation that some children with isolated, classic KS were born to consanguineous parents further suggested that single-gene inborn errors of immunity might underlie such cases (Sahin et al., 2010), as seen in children with other isolated life-threatening infectious diseases (Casanova and Abel, 2007; Alcaïs et al., 2010). Accordingly, autosomal recessive complete STIM1 deficiency was found in a Turkish child with fatal, isolated KS (Byun et al., 2010). Collectively, these findings provided evidence that classic KS in childhood, whether isolated or associated with other infections, may result from single-gene inborn errors of immunity to HHV-8. The three known KS-predisposing genes, IFNGR1, WAS, and STIM1, are pleiotropic and expressed in various cell types, including leukocytes and nonhematopoietic cells. It thus remains unknown which specific cell types and molecular pathways are critical for the effective control of HHV-8 infection. We therefore searched for new genetic etiologies of classic KS in childhood. We report here the discovery and characterization of autosomal recessive complete OX40 deficiency in a young adult with childhood-onset classic KS, suggesting a nonredundant role of OX40 in T cell–mediated defense against HHV-8.     

Absence of Kaposi sarcoma among Ethiopian immigrants to Israel despite high seroprevalence of human herpesvirus 8

OBJECTIVE: To determine the prevalence of Kaposi sarcoma (KS) and human herpesvirus 8 (HHV-8) seropositivity in Ethiopian Jewish immigrants to Israel. METHODS: A Western blot assay was used to determine the seroprevalence of HHV-8 in serum samples from 202 randomly selected human immunodeficiency virus (HIV)-negative and 47 HIV-positive Ethiopian immigrants; samples were obtained on arrival of the immigrants in Israel. The Israel Cancer Registry provided comprehensive data on the occurrence of KS among Ethiopian immigrants and in the non-Ethiopian population of Israel. RESULTS: A total of 39.1% and 57% of the HIV-negative and HIV-positive Ethiopians, respectively, were infected with HHV-8 (P<.03). However, none of the Ethiopians examined and none of the other HIV-negative Ethiopians among about 45,000 immigrants had KS. Moreover, only 1 (0.85%) of 118 Ethiopian patients with acquired immunodeficiency syndrome (AIDS) developed KS compared with 49 (12.5%) of 391 non-Ethiopian AIDS patients (P<.001). CONCLUSION: Although HHV-8 infection is common in Ethiopian Jewish immigrants to Israel, these patients almost never develop KS, in marked contrast to the strong association usually observed. The mechanism behind this population's unique protection requires further study.     

Virology,pathogenetic mechanisms,and associated diseases of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8)

Kaposi sarcoma-associated herpesvirus (KSHV) is a recently discovered and characterized member of the herpesvirus family. It is one of a few viruses proved to be associated with tumorigenesis in humans. Its causal association with 4 clinical and epidemiologic variants of Kaposi sarcoma (classic, endemic, iatrogenic, and acquired immunodeficiency virus-associated) as well as with several lymphoproliferative disorders (notably primary effusion lymphoma and multicentric Castleman disease) is reviewed critically. Issues related to the epidemiology, transmission, and molecular and serologic diagnosis are discussed. Several intriguing oncogenic mechanisms of KSHV infection have been identified. These are often dependent on the interaction of KSHV with other viruses, such as human immunodeficiency virus, Epstein-Barr virus, or both. However, important problems remain and once resolved will substantially enhance our understanding of oncogenesis in general and viral-induced oncogenesis in particular. This may also translate into improved treatment and perhaps prevention of this common and intriguing viral infection.     

Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca²⁺ entry. STIM1 mRNA splicing, protein production, and Ca²⁺ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.Kaposi sarcoma (KS) is an angiogenic, inflammatory neoplasm first described by Moritz Kaposi (1872). The etiology of KS was unknown until Chang et al. (1994) isolated KS-associated herpesvirus, also known as human herpesvirus (HHV)-8, from KS lesions. Cells of endothelial origin are the principal targets of HHV-8 infection and the major components proliferating in KS lesions (Ganem, 2010). It has been clearly established that all forms of KS are associated with HHV-8 (Dupin et al., 1995; Moore and Chang, 1995; Schalling et al., 1995; Chang et al., 1996). Infection with HHV-8 is necessary but not sufficient for the development of KS. Despite the high seroprevalence of HHV-8, at up to 30% in the Mediterranean Basin (classic KS) and 70% in sub-Saharan Africa (endemic KS), the incidence of KS is very low (Boshoff and Weiss, 2001). Individuals with acquired immunodeficiency caused by HIV infection (epidemic KS; Martellotta et al., 2009) or immunosuppression after organ transplantation (iatrogenic KS; Lebbé et al., 2008) are at a much higher risk of developing KS than the general population. Host factors in other patients are therefore likely to play a critical role in determining the outcome of HHV-8 infection, including the development of KS in particular.As a first approach to testing the hypothesis that KS may result from inborn errors of immunity to HHV-8 in some patients (Casanova and Abel, 2007), we focused on classic KS in childhood. Classic KS is exceedingly rare in children, with only 30 cases reported since 1960, and follows a disseminated and often lethal course (Dutz and Stout, 1960; Bisceglia et al., 1988; Akman et al., 1989; Zurrida et al., 1994; Erdem et al., 1999; Landau et al., 2001; Ferrari et al., 2002; Hussein, 2008). We previously reported two children from the Mediterranean Basin with KS caused by an underlying primary immunodeficiency, one with autosomal recessive complete IFN-γR-1 deficiency (Camcioglu et al., 2004) and the other with X-linked recessive Wiskott-Aldrich syndrome (Picard et al., 2006). These children had several other clinical phenotypes, including mycobacterial disease in the IFN-γR1–deficient child and EBV-driven lymphoma in the child with Wiskott-Aldrich syndrome. These two cases provided the first evidence that classic KS in childhood may result from inborn errors of immunity, at least in children with multiple infectious and tumoral phenotypes, including KS.More recently, we described three unrelated Turkish children with classic KS in the absence of any other infectious or tumoral phenotype, each born to consanguineous parents (Sahin et al., 2010). This suggested that classic KS in children with no overt signs of immunodeficiency might also result from single-gene defects impairing HHV-8 immunity. Because the age of onset, clinical features, and outcome of KS reported in previous studies differ from child to child (Dutz and Stout, 1960; Bisceglia et al., 1988; Akman et al., 1989; Zurrida et al., 1994; Erdem et al., 1999; Landau et al., 2001; Ferrari et al., 2002; Picard et al., 2006; Camcioglu et al., 2004; Hussein, 2008; Sahin et al., 2010), we further hypothesized that the single-gene inborn errors of immunity underlying classic KS in children are heterogeneous. Using the recently developed whole-exome sequencing approach, which has been used to determine the genetic basis of other rare Mendelian disorders in small numbers of affected individuals (Choi et al., 2009; Hoischen et al., 2010; Lalonde et al., 2010; Ng et al., 2010; Walsh et al., 2010), we focused our investigation on a single Turkish child with early-onset disseminated KS that eventually ran a lethal course.     

Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma

Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein-coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.     

Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice

Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-λ, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell-derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell-associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents.     

人类第6型疱疹病毒感染与特发性血小板减少性紫癜

探讨人类第６型疱疹病毒（ＨＨＶ－６）感染与特发性血小板减少性紫癜（ＩＴＰ）的关系。方法采用聚合栈 反应（ＰＣＲ）方法检测１０５例ＩＴＰ患者骨髓单个核细胞（ＢＭＭＮＣ）ＨＨＶ－６ＤＮＡ及部分患者微小病毒Ｂ１９、巨细胞病毒（ＨＣＭＶ）ＤＮＡ序列;用竞争性ＥＬＩＳＡ方法检测６６例ＩＴＰ患者血小板相关抗体（ＰＡＩｇ）,并采用间接免疫荧光法动态观察１９例ＩＴＰ患者抗ＨＨＶ－６血清抗体滴度变化。结果①ＩＴＰ患     

Human herpesvirus 8, Kaposi's sarcoma,and associated conditions

HHV-8 is a recently identified human herpes virus that can produce tumors, most often in immune compromised hosts. The virus is most closely associated with Kaposi's sarcoma, but is also clearly associated with primary effusion lymphomas and multicentric Castleman's disease. The prevalence of HHV-8 infection varies considerably, but is highest among men who have sex with men and others with histories of sexually transmitted diseases and high numbers of lifetime sexual partners. HHV-8 is shed in saliva, and less commonly in genital secretions. Treatment of HHV-8 associated diseases includes reversal of immune compromise either via discontinuation of immunosuppressives or immune reconstitution via antiretroviral regimens. Specific antiviral drug inhibit HHV-8 replication, and can result in responses in certain HHV-8-associated conditions.     

Course and diagnosis of pulmonary Kaposi sarcoma in patients with AIDS

Diagnosis of pulmonary Kaposi's sarcoma can be difficult. Clinical findings and chest X-rays are non-specific and endobronchial diagnostic in about 50% of cases. Additional concomitant infectious complications are frequent. Symptomatic pulmonary Kaposi's sarcoma most oftenly is progressive and has a poor prognosis. Preliminary data suggest effective palliation with radio- and chemotherapy and an improved survival time in selected cases. We present six cases of proven pulmonary Kaposi's sarcoma and discuss clinical course and diagnostic difficulties. Based on this view we propose a diagnostic approach to warrant therapeutic success.     

Isolated intraparotid Kaposi sarcoma in human immunodeficiency virus type 1 infection

Isolated Kaposi sarcoma (KS) of the parotid gland is an uncommon but distinct entity in patients with human immunodeficiency virus type 1 (HIV-1). A 30-year-old white homosexual man in whom HIV-1 had been diagnosed 2 years previously developed right parotid gland enlargement in the absence of constitutional symptoms. He had been taking zidovudine, lamivudine, and indinavir; his CD4 cell count was 0.297 x 10(9)/L, and HIV-1 RNA load was 47 copies/mL. After surgical excision of the parotid gland, biopsy findings disclosed KS of an intraparotid lymph node. A literature review revealed 6 other men with HIV-1 and isolated parotid KS. To our knowledge, our patient is the first to have received triple antiretroviral therapy with excellent immunological and virological response and parotid gland enlargement that might reflect immune reconstitution. Even in the absence of skin or other lesions, KS should be considered in the differential diagnosis of parotid gland enlargement in patients with HIV-1, even in those who are responding to highly active antiretroviral treatment.     

终末期肾病患者的获得性免疫缺陷和甲状旁腺激素水平的关系

目的 观察维持性血液透析的终末期肾脏病(end-stage renal disease,ESRD)患者的B和T细胞亚群分型,评价T细胞功能与血浆甲状旁腺激素(parathyroid hormone,PTH)之间的相关性.方法 检测接受血液透析和腹膜透析的257例ESRD患者血常规淋巴细胞计数,根据患者是否血液透析和血P...     

人类疱疹病毒8型相关疾病及致病机制研究进展

人类疱疹病毒8型(HHV-8)也被称为卡波西肉瘤相关的人类疱疹病毒(KSHV)。HHV-8与多种疾病特别是淋巴细胞相关的恶性疾病相关。本文对近年来HHV-8相关的微生物学特征、流行病学特点、传播途径、相关疾病及致病机制的研究进展作一介绍。     

新疆维吾尔族、汉族妇女宫颈病变人类染色体端粒酶基因扩增与人乳头瘤病毒感染相关性研究

目的:探讨新疆地区维吾尔族(维族)、汉族妇女宫颈病变脱落细胞中人类染色体端粒酶基因(human telomerase gene,hTERC)的表达差异及其与人乳头瘤病毒(human papillomavirus,HPV)高危亚型感染的相关性。方法:采用荧光原位杂交技术,比较50例维族和52例汉族宫颈病变患者hTERC基因扩增情况,同时检测HPV感染情况。结果:维族宫颈病变患者hTERC基因扩增率为62.00%,汉族宫颈病变hTERC基因扩增率为51.92%。随病变进展,维、汉族宫颈病变患者hTERC基因扩增均明显增加。维、汉族宫颈癌hTERC基因平均扩增倍数,在HPV各亚型感染组间差异无统计学意义(P>0.05),但在HPV多重感染和单一感染间差异有统计学意义(P<0.05)。维族宫颈病变总hTERC基因扩增倍数与汉族差异有统计学意义(P<0.05)。结论:hTERC基因扩增与高危型HPV感染有关,可能是宫颈癌进展的预测指标;多重HPV高危亚型感染可能是维族宫颈癌发病率高的原因之一。     

新疆维吾尔族、汉族妇女宫颈病变人类染色体端粒酶基因扩增与人乳头瘤病毒感染相关性研究

目的:探讨新疆地区维吾尔族(维族)、汉族妇女宫颈病变脱落细胞中人类染色体端粒酶基因(human telomerase gene,hTERC)的表达差异及其与人乳头瘤病毒(human papillomavirus,HPV)高危亚型感染的相关性.方法:采用荧光原位杂交技术,比较50例维族和52例汉族宫颈病变患者hTERC基因扩增情况,同时检测HPV感染情况.结果:维族宫颈病变患者hTERC基因扩增率为62.00%,汉族宫颈病变hTERC基因扩增率为51.92%.随病变进展.维、汉族官颈病变患者hTERC基因扩增均明显增加.维、汉族宫颈癌hTERC基因平均扩增倍数,在HPV各亚型感染组间差异无统计学意义(P＞0.05),但在HPV多重感染和单一感染间差异有统计学意义(P＜0.05).维族宫颈病变总hTERC基因扩增倍数与汉族差异有统计学意义(P＜0.05).结论:hTERC基因扩增与高危型HPV感染有关,可能是宫颈癌进展的预测指标;多重HPV高危亚型感染可能是维族宫颈癌发病率高的原因之一.     

Quantitation of human herpesvirus 8 (HHV-8) antibody in patients transfused with HHV-8–seropositive blood

BACKGROUND: Human herpesvirus 8 (HHV-8) is endemic in Uganda where seroprevalence is approximately 40%. In a previous study, Ugandan patients receiving blood transfusions had multiple serum specimens collected for 6 months after transfusion to monitor for HHV-8 infection. It was observed that several HHV-8–seronegative patients were unexpectedly HHV-8 seropositive after blood transfusion.
STUDY DESIGN AND METHODS: This study measured HHV-8 antibody in serially collected serum specimens from 542 patients who received transfusions and evaluated the risk of HHV-8 infection as a function of HHV-8 antibody levels in the donors.
RESULTS: HHV-8 antibody was observed in 52% of patients transfused with HHV-8–seropositive blood in amounts that corresponded with their donor's antibody titer and waned within 40 days. Higher levels of passive HHV-8 antibody in patients who received transfusions appeared to be associated with a lower risk of HHV-8 infection.
CONCLUSION: The source of transient antibody in patients who received transfusions was determined to be the transfused blood. Donors with higher HHV-8 antibody titers may have been less likely to have infectious virus in the blood.     

Interferon alpha 2C in the treatment of 2 patients with AIDS-associated Kaposi sarcoma

Two patients with AIDS and histologically confirmed Kaposi's sarcoma were treated with 3 X 10(6) U/m2 interferon alpha 2C (rIFN alpha 2C) subcutaneously three times a week. In both cases remissions (7 weeks and more than 9 months) of the tumour lesions were achieved and in one case pretherapeutic moderate thrombocytopenia improved. The positive serum antibody titres to HTLV III-virus showed no conversion. Except for fever (below 39 degrees C) during the first two weeks of IFN treatment in both patients, therapy-requiring hypotonia, mild depression, leucopenia (WHO grade 1) and thrombocytopenia (WHO grade 2) in one patient, no side effects were observed. All the above-mentioned features were reversible after termination of treatment. Further studies to optimize the dosage of rIFN alpha 2C and its time schedule in the treatment of Kaposi's sarcoma in patients with AIDS are recommended.     

血液透析患者血浆同型半胱氨酸与心血管疾病的关系

目的研究血液透析患者血浆同型半胱氨酸浓度、影响因素及与心血管疾病的关系。方法选择维持性血液透析患者65例和健康对照30例,记录患者心血管并发症,采用荧光偏振免疫分析法测定血浆总同型半胱氨酸（tHcy）浓度。结果血液透析患者高同型半胱氨酸血症的发生率为89.2%。有心血管并发症组Ln（tHcy）明显高于无并发症组,两组Ln（tHcy）、三酰甘油、前白蛋白差异具有统计学意义（P〈0.05）,其余指标差异没有统计学意义（P〉0.05）。高tHcy血症与透析间期体重增加、血浆白蛋白及三酰甘油有关。糖尿病患者心血管并发症的发病率高于非糖尿病者（P〈0.05）,有心血管并发症组和没有并发症组之间tHcy差别没有统计学意义（P〉0.05）。多因素逐步回归分析显示高tHcy血症是血液透析患者心血管疾病的危险因素,而前白蛋白是保护因素。结论维持性血液透析患者存在高tHcy血症,高tHcy是其发生心血管疾病的危险因素。